The lymphatic system is an essential part of the vascular system, with multitasking functions to absorb fats and fat-soluble nutrients in the digestive system; eliminate excess extravasated fluid from blood vessels as part of homeostasis; and facilitate immune responses by surveilling pathogens and enabling immune cell transit within lymph fluid (1–6). Dysfunctional lymphatic vessels and/or lymph nodes can result in build-up of lymph fluid in the interstitial space, resulting in lymphedema (LE), which initially manifests as edema in the extremities and progresses to fibrosis, with eventual impaired limb function, pain, depression, and increased cellulitis risk. From 2012 through 2017, there were more than 165,000 hospital admissions due to LE, 92% of which were associated with cellulitis in the United States (US) (7). While primary LE is genetic, most cases are secondary and related to obesity, or acquired following radiotherapy, surgery, trauma, or infections. Approximately 15.5% of breast cancer survivors develop LE, with 24% having LE 7 years postdiagnosis (2, 8, 9). Decreased lymph flow leads to the accumulation of proinflammatory cytokines that continuously activate nociceptors responsible for pain, resulting in a chronic inflammatory response that can be associated with chronic pain and disease (4–6). Chronic rheumatoid arthritis (RA) and complex regional pain syndrome (CRPS) appear to be associated with impaired lymphatic function (4, 10–12).

Therapy targeting LE aims to reduce lymphatic fluid in the affected limb to improve function and prevent progression (2, 13–15). The most widely accepted treatment is complex decongestive therapy (CDT), which primarily involves a specialized gentle type of therapeutic massage known as manual lymphatic drainage (MLD), followed by exercise, compression therapy, and skin care (1, 2, 13, 14). Randomized controlled trials (RCTs) have demonstrated statistically significant improvements in the incidence of LE and pain following MLD in patients with breast cancer (p = .02) (15). Pneumatic compression therapy (PCT) is part of CDT and usually involves a garment inflated by a pump over the affected limb to mimic MLD in the home setting (16). Multiple studies have demonstrated that significant edema reduction occurred with PCT (16–19).

Over the past decade, improved techniques in lymphatic imaging have demonstrated lymphatic contractile function following LE treatment. Near-infrared fluorescence lymphatic imaging (NIRFLI) visualizes lymphatic function and movement in real-time, by tracing the flow of intradermal injections of indocyanine green (ICG) administered to relevant anatomic sites (6, 16, 20–24). NIRFLI has shown that lymphatic function improves following MLD (21) and PCT (16, 23, 24). However, while improved lymphatic pumping, measured by increased pulsatile frequencies of lymphatic vessels, has been consistently observed with NIRFLI, lymphatic mapping of drainage patterns is highly heterogeneous and variable from one patient to the next, even among the same affected anatomic regions (25). Lymphatic vessels can both converge into one and split into multiples at the same site, and their drainage pathways and rates vary enormously.

A novel PCT medical device is now available over the counter for home use that involves a 16-chamber mat on which patients lie down supine to receive automated MLD therapy (AMLDT). The US Food and Drug Administration classifies it as a Class II medical device indicated for temporary pain reduction in people with good health, excluding pregnancy, heart/vascular problems, acute pulmonary edema, infections, injury at/near the application site, where increased venous/lymphatic return is undesirable, spinal cord/back injuries, and bronchial asthma. Herein, 4 case reports describe a patient with traumatic CRPS and LE, a healthy patient, a breast cancer survivor with chronic pain, and a patient with a history of abdominal surgery. They serve as proof of concept to assess how AMLDT impacts lymphatic function and also demonstrate their unique lymphatic drainage patterns. Each case underwent NIRFLI while receiving a single session of AMLDT to determine whether AMLDT improved lymphatic pumping, specifically pulsatile frequency. Secondarily, patient feedback on AMLDT and its effect on pain was assessed to understand patient perspective.

All 4 patients presented at a university outpatient clinic in August 2023 and provided their written informed consent. The Committee for the Protection of Human Subjects approved the study protocol (HSC-MS-23-0093) on June 22, 2023. In all cases, vital signs were normal at time of presentation.

Each case underwent a NIRFLI session with concurrent AMLDT. NIRFLI assessed lymphatic flow at baseline with the patient in a supine and prone position, during 1 h of AMLDT with the patient in a supine position, and 30–60 min posttreatment with the patient in a supine and prone position. At the start of the imaging session, patients reported pain using a Visual Analogue Scale (VAS, based on a score between 0 and 10, with 0 having no pain and 10 having the most pain). Each patient put on a “bikini” bottom, and women wore a bikini top, to afford maximal visualization of dermal lymphatic regions.

The ICG (25 mg vial) was reconstituted with 10 ml sterile water and further diluted in sterile saline immediately prior to administration. The final concentration of 0.32 mM provided 25 μg ICG/injection, with each injection of 0.1 cc made at the anatomical injection sites shown in Figure 1. Tables 1, 2 also describe the anatomic injection sites of each case. Alcohol wipes were used to clean each injection site before intradermal injection. Each patient received 32–36 injections. NIRFLI was accomplished using a custom system consisting of a Gen III military-grade intensifier coupled to a frame transfer, 16-bit camera with 200 ms exposure times (20). Initial NIRFLI imaging lasted for 60 min to assess the drainage of ICG laden lymph from each injection site toward regional nodal basins. Vital signs of blood pressure, pulse rate, respiratory rate, temperature, and redness or inflammation at the injection site were monitored and recorded at baseline (before ICG injection) and 15 and 30 min after injection. NIRFLI imaging continued during the 1-h AMLDT session. After AMLDT, imaging continued for another 30–60 min. Patients reported any posttreatment pain and provided their feedback on the AMLDT device.

The AMLDT system (Neuroglide, Eva Medtec, Bloomington, MN) offers 3 treatment focus zones (Upper and Lower Back/Neck, Upper Back/Neck, and Lower Back) and 3 pressure settings (mild, medium, and intense). The back/neck pad has 16 air channels precisely timed to produce a sequential inflation/deflation pressure cycle, mimicking the stretch and release action provided by therapeutic MLD-like massage to manipulate soft tissue, relieve pain, and increase circulation. The AMLDT system is intended for use on a flat, firm surface at home.

Each patient lay supine on the pad with their heads centered on the supportive pillow section, ensuring that there were no gaps between their neck and the pad. They received 1 h of intense AMLDT to the upper and lower back/neck.

All 4 cases completed the NIRFLI and AMLDT session without complications or adverse events. Tables 1, 2 report the lymphatic pulsing frequencies for visualized vessels draining at each injection site (listed in top down order as depicted in Figure 1) 1 h before AMLDT, during treatment, and 30–60 min posttreatment. When multiple vessels drained at an injection site, a pulsing frequency for each is reported. AMLDT appeared to alter lymphatic contractility; both increased and decreased pulsing frequencies were observed, including in healthy, nonaffected limbs (Case 2). Pulsing frequencies were very heterogeneous from one case to the next and also varied within anatomic regions of the same patient. Figure 2 shows avatar examples of the heterogeneity of the directional changes in pulsing frequencies on the backs of each case.

In Case 1, NIRFLI demonstrated lymphatic dysfunction with dermal backflow, in which lymph moves into the lymphatic capillary bed instead of unidirectionally into lymphatic collector vessels, and tortuous vessels in the right upper lateral shin and foot. Generally, injection sites on the arms, anterior abdomen, and anterior legs of the front of his body saw increases in pulsatile frequency during AMLDT and posttreatment, compared to baseline values (Table 1). Most notably, in the CRPS-affected right leg, the pulsatile frequency nearly doubled during AMLDT from 0.53 pulses/min to 0.96 pulses/min and remained higher than baseline during posttreatment NIRFLI (0.75 pulses/min). At the umbilical region, drainage patterns varied, with the inferior umbilical injection sites and possibly the left superior injection site draining to the inguinal region, while the right superior umbilical injection site drained towards the axilla. On his back, the injections at the thoracic level drained inferiorly and laterally and then traveled anteriorly towards axilla. Supplementary Videos 1A and 1B depict NIRFLI before and after AMLDT on his back, where lymphatic collectors traveled from medial-to-lateral in a dermatomal pattern and pulsatile frequencies decreased after treatment, except in the 2nd to 4th lumbar areas where no data was obtained (Table 2).

Case 2 (healthy patient) had increases in pulsatile frequencies on his arms, thighs, and lower legs in response to treatment (Table 1). Most notably, pulsatile frequency more than tripled in his right arm from 1.84 pulses/min before AMLDT to 5.82 after treatment. On the back, however, pulsatile frequencies generally decreased after treatment, except for his right lumbar area, where the rate tripled from 0.39 pulses/min before treatment to 1.17 pulses/min after treatment (Table 2).

Case 3 notably had a lack of pulsing or lack of data at most injection sites at the umbilical region, legs, and back, and (particularly) near the anterior and posterior neck (Tables 1, 2). One small, unusual vessel was observed on her left arm, which previously experienced a fracture and was the side corresponding to her breast cancer. Her middle umbilical-to-axilla sites saw sharp decreases in pulsatile frequencies after AMLDT, while sites on her right leg and right posterior thoracic area increased.

NIRFLI did not show pulsing on the umbilical sites of Case 4, expect for one tortuous vessel that was captured on the left lower umbilical-to-inguinal site during AMLDT, with a low rate of 0.30 pulses/min (Table 1). Pulsing frequencies notably increased on both her arms during and after treatment, with the posttreatment rates 3.5 higher in her right arm and 2.6 times higher in her left arm compared to baseline. In her legs, however, pulsatile frequencies decreased. On her back, rate increases were observed at the most superior injection at the posterior thorax on the right, both superior lumbar sites, and the left inferior lumbar site (Table 2). All other back sites demonstrated decreased rates after AMLDT, or data was unavailable.

From the patients' subjective perspective, AMLDT was reported as soothing and/or relaxing. Decreased pain was reported in the 3 cases that reported pretreatment pain. The VAS scores for Case 1 decreased from 5 to 2 after treatment, in Case 3 from 2 to 0, and in Case 4 from 4 to 0. Case 2 did not report any pain during this study.

We describe 4 very heterogenous cases with and without LE or risk of LE, all of whom demonstrated altered lymphatic movement (as shown by NIRFLI) after 1 h of AMLDT. AMLDT provided pain relief to those affected with chronic pain. AMLDT is intended for pain relief; thus, the patient feedback in these case reports is not surprising, but a further discussion of the association of the lymphatic system with chronic pain is warranted, especially in the context of Case 1. A companion paper will explore the effect of AMLDT on his CRPS and LE in greater detail.

Pulsatile frequences increased and decreased in all cases, suggesting changes in lymphatic contractility trends, and findings were not necessarily consistent across the anatomic region of the same patient (Tables 1, 2). The decreased pulsatile frequencies generally observed on the back (Table 2, Figure 2), and the finding that back lymphatic collectors travel from medial to lateral along dermatomal patterns (Supplementary Videos 1A and 1B) was clearly demonstrated, but it is not unusual for unexpected lymphatic movements and drainage patterns to occur in both healthy-appearing and unaffected anatomic regions (22, 25). High-quality lymphoscintigraphy has shown that in over 3,000 patients with melanomas, the trunk of the body frequently demonstrated drainage across the body's midline (25), and superficial lymph flow moving laterally and a deep lymph flow moving medially has been reported in the back (26). With NIRLFI, improved imaging technology now captures real-time lymphatic movement, and our understanding of lymphatic movement is undergoing a paradigm shift from defining “normal” flow in healthy patients towards the observation that every patient has their own unique watershed zones that may not be static over time. This evolving evidence base will allow for more targeted therapeutic outcomes and advance personalized medicine.

The unexpected, decreased pulsatile frequencies observed in the back do not appear to be a limitation of the AMLDT pumping technique (Figure 2). What is unique to the AMLDT mat used in this study, compared to other MLD/PCT devices, is that the treatment not only has an effect upon limb lymphatic contractility, but also along the back, with the patient resting in a supine position, rather than seated (16–19). We speculate that the relaxation induced by AMLDT, coupled with the gravity exertion on the back, resulted in decreased pulsatile frequencies, similar to a lower resting heart rate. Both extrinsic and intrinsic forces are responsible for lymphatic movement, with the latter driven by lymph vessel distension. The lymphangion, the pumping unit bounded by valves located along collector lymphatic vessels, is known to function similarly to the cardiac pump in the heart, by increasing intrinsic contractility to adapt to output pressure elevation in response to increased pressure and/or gravitational load, producing a systolic and diastolic phase (27–31). This intrinsic pumping mechanism varies contractility rates and lymph flow to respond to environmental factors and pressure gradients. Jamalian et al. (29) supported Guyton's subatmospheric theory, which hypothesizes that a lymphatic contraction produces a suction effect (in the presence of competent lymphatic valves) upon relaxing of decreased pressure downstream, opening the inlet valve and allowing for the filling of lymphatic fluid due to the low upstream pressure from the previous section of vessel (32, 33). Therefore, the relaxation of the collecting vessel following contraction is essential to drawing fluid from the interstitium. Since our patients received AMLDT to the back, it is possible that the gravitational load moved a sufficient volume of fluid during treatment, decreasing output pressure and resulting in decreased contractility and pulsatile frequencies. Additionally, mapping of lymphatic drainage following MLD applied to improve LE of the upper back has shown that MLD essentially finds an alternative, efficient route to evacuate accumulated lymph interstitial fluid to an area not affected with LE (34). These alternative lymphatic drainage pathways are rerouted, as needed, on an individual basis, further explaining the heterogeneity of patient data. Further study of AMLDT on the back of the body is suggested to confirm these findings.

Only 4, noncomparative cases are reported in this paper, and so statistical analysis was not performed. While the cases represent different health states and LE status and may not be generalizable to the general population, they nonetheless support the heterogeneous anatomy and function of the lymphatic system that previously has been reported in the literature (22, 25) and show the change in lymphatic contractility from before AMLDT (baseline) to posttreatment. Each patient only received 1 treatment session of AMLDT, and so, the long-term effect of AMLDT is unknown. In a study of 10 survivors of head and neck cancer with LE, NIRFLI demonstrated that daily use of advanced PCT for 2 weeks improved lymphatic function in all patients and eliminated or reduced dermal backflow in 6 of the 8 patients who had had backflow (23). There remains a need to better characterize the propulsion frequency over time. Future comparative studies could potentially control for time variations by imaging controls over the same timeframe, with a longer follow-up time, and in the same positions but without AMDLT. This proof-of-concept study suggests that, in addition to reducing pain, AMLDT appears to impact lymphatic contractility of the lower and upper extremities, umbilical region/trunk, and back. The resting, supine position required for AMLDT likely decreased contractility rates and lowered pulsatile frequency during and after treatment, further supporting that lymphangion pumps respond to intrinsic and extrinsic forces similar to the cardiovascular system and have varying contractile rates in response to changing environmental pressures. Further research on the effect of AMLDT on the back and on patients with LE and chronic pain is warranted.